The oral administration of pharmaceutically active substances in conventional solid forms such as tablets or capsules is often problematic in special patient groups who have difficulties in swallowing said solid forms whole, for example children and older patients. For these patients, suitable dosage forms for drugs may be e.g. liquid forms, e.g. solutions, suspensions, syrups or emulsions, or alternative solid forms such as chewable tablets, effervescent tablets or soluble tablets. These dosage forms usually do not prevent a perceptible degree of exposure of the active substance to the taste buds, which is a major problem when the active substance has a unpleasant and/or bitter taste. In such cases, the active substance has to be taste-masked, so that the dosage form becomes palatable, thereby reducing the risk that the patients refuse to take the medicament.
It is a great challenge to taste-mask extremely bitter tasting active substances such as macrolides, e.g. erythromycin or clarithromycin, especially when comprised in suspensions. Conventional taste masking techniques such as the addition of sweeteners such as sugar, artificial sweeteners, fruit aromas, thickeners and amino acids, often fail to give the pharmaceutical composition an acceptable taste.
It is mostly that portion of the active substance in such dosage forms which is dissolved in the saliva and/or in the liquid for administration that generates the unpleasant taste. To overcome this problem, it is common to influence the solubility of said active substance in such a way that only a small portion of said substance, or even none of it, will dissolve in a suspension, or in the mouth. This is often achieved by embedding the bitter tasting active substance in a special embedding material or by coating said drugs. These techniques have, however, their limitations and usually prove effective only for moderately bitter drugs. The embedding and/or coating techniques may also adversely impact the desired release of the active substance into the digestive tract to achieve good bioavailability.
To ensure sufficient bioavailability of the active substance, one may use coatings, e.g. lipid and/or wax coatings that retard the dissolution of the active substance for a short period of time, or slightly retarding polymer films or the like. These coatings, however, can only provide satisfactory taste-masking if said suspensions are administered shortly after their reconstitution, i.e. after dispersion in an aqueous medium.
International Application WO 93/12771 discloses another technique for taste masking by coating core particles comprising e.g. clarithromycin with a polymeric coating layer comprising a prolamine fraction derived from grain proteins, preferably zein, and plasticizers being preferably fatty acids, wherein said coating layer is relatively thick.
Another technique is described in International Application WO 00/76479 A1, wherein the bitter tasting active substance is embedded in a taste-masking matrix composed of a combination of two enteric polymers, i.e. a methacrylic acid copolymer and a phthalate polymer, which is optionally coated.
Most of the conventional taste masking techniques fail to provide satisfactory taste masking in a suspension which is required to maintain its pleasant taste over an extended period of time, e.g. for at least 1 to 2 weeks as a reconstituted suspension. In such cases, film-coatings with a pH-related solubility are commonly used. This means that the pH value in the suspension is adjusted to a value at which the film-forming component, e.g. the film-forming polymer, comprised in the film-coating is not soluble. The pH value changes upon administration, and depending on the coating material used, the active substance will be released either into the stomach in the case that the coating is acid-soluble, or into the intestines, e.g. the small intestine, in the case of base-soluble enteric or gastro-resistant coatings.
International Application WO 91/16043 discloses the application of a polymeric coating being soluble only at a pH of 5 or greater to a core particle, and the addition of an acidic compound to the formulation to reduce or prevent the dissolution of the coating membrane in the oral cavity.
The proportioning of said film-coatings is, however, critical: film-coatings which are too strong and/or thick, may retard the rate of the drug release in the gastrointestinal tract to an extent which would be unacceptable for conventional immediate release formulations.
Another problem is that the above mentioned film coatings, e.g. polymer coatings, are never entirely “leak-proof”, which means that even with intact film coatings a portion of the active substance is always released from the coated particles by way of diffusion into the suspension, which herein is called “leakage”. This may lead to the sensation of a bitter taste after ingestion.
Generally, the pH value of the liquid component of pharmaceutical compositions such as suspensions is adjusted to a value that will ensure that the coating will not be dissolved and/or etched. However, if the taste-masked active substance possesses a good solubility in this pH range, this will, in turn, increase the diffusion of the unpleasant-tasting active substance and thereby cause leakage into the suspension and/or in the mouth after oral administration.
Additionally, conventional techniques for preparing a palatable liquid dosage form comprising an unpleasant and/or bitter tasting drug may involve costly and complicated preparative methods.
Accordingly, it is an object of the present invention to provide a liquid dosage form, particularly a suspension, comprising coated particles containing an unpleasant and/or bitter tasting pharmaceutically active substance, which is palatable and which keeps its palatability even over a prolonged period of time after being reconstituted e.g. by the addition of water. Additionally, said suspension should exhibit satisfactory bioavailability, i.e. a rapid release of the active substance in the gastro-intestinal tract after oral administration.